Cyclopentenone prostaglandins of the J series inhibit the ubiquitin isopeptidase activity of the proteasome pathway

Electrophilic eicosanoids of the J series, with their distinctive cross-con jugated alpha,beta -unsaturated ketone, inactivate genetically wild type tu mor suppressor p53 in a manner analogous to prostaglandins of the A series. Like the prostaglandins of the A series, prostaglandins of the J series ha ve a structural determinant (endocyclic cyclopentenone) that confers the ab ility to impair the conformation, the phosphorylation, and the transcriptio nal activity of the p53 tumor suppressor with equivalent potency and effica cy. However, J series prostaglandins have a unique structural determinant ( exocyclic alpha,beta -unsaturated ketone) that confers unique efficacy as a n apoptotic agonist. In seeking to understand how J series prostaglandins c ause apoptosis despite their inactivation of p53, we discovered that they i nhibit the ubiquitin isopeptidase activity of the proteasome pathway. In th is regard, J series prostaglandins were more efficacious inhibitors than re presentative members of the A, B, or E series prostaglandins. Disruption of the proteasome pathway with proteasome inhibitors can cause apoptosis inde pendently of p53. Therefore, this finding helps reconcile the p53 transcrip tional independence of apoptosis caused by Delta 12-prostaglandin J(2). Thi s. discovery represents a novel mechanism for proteasome pathway inhibition in intact cells. Furthermore, it identifies isopeptidases as novel targets for the development of antineoplastic agents.